The goals of this proposed research are to provide information on the effects of inhalational anesthetics (halothane, enflurane and isoflurane) and calcium antagonists (verapamil, nifedipine and diltiazem) on cardiac electrophysiology. The following hypothesis will be tested: selected calcium antagonists may differentially potentiate direct negative inotropic and chronotropic effects of general anesthetics. Since all of these agents alter slow inward current (depression varies among these agents), and perhaps change intracellular calcium stores and release, it is essential to examine individual effects on a) calcium influx, b) mobilization of Ca++ from sarcolemma and internal (SR) pools c) intracellular free Ca++; d) cell electrophysiology and e) contractile characteristics and cardiac automaticity. A variety of methods have been selected to test the above parameters including: 45Ca influx and efflux studies; measurement of the free intracellular Ca++ with aequorin; double micro-electrode voltage clamping technique, and standard methods for the measurements of transmembrane potentials, conduction velocity, membrane responsiveness and contractile force measurements. Individual contributions of calcium entry and calcium release to the intracellular free calcium will be examined with a use of ryanodine, (which inhibits SR release of Ca++) and specific calcium agonists Bay k 8644 and CGP 28392. In order to examine differences in anesthetic depression and their interaction with calcium antagonist on cardiac automaticity, conduction and contractility, tissues to be studied will include: the sino-atrial node, Purkinje fibers and ventricular papillary muscles. The increased use of calcium antagonists is due to the increasingly recognized importance of calcium as a mediator of normal myocardial function as well as myocardial injury induced by myocardial ischemia. Since patients receiving calcium antagonists may require either cardiac or non-cardiac operations, it is important to recognize potential interactions between these drugs and the most commonly used anesthetic agents. This research proposal is specifically aimed to improve our knowledge of their actions and interactions. Our long term objective is to more effectively understand and use their diverse actions and pharmacologic properties.